Dysregulated bone remodelling is a major part of the pathology of a number of diseases. In such conditions accelerated production and activation of the bone resorbing osteoclast population results from an as yet unidentified aberrant network of mediators. In the past ten years, the major signalling pathways and transcription factors controlling the commitment and differentiation of haematopoietic stem cells and monocyte/macrophage precursors to the osteoclast lineage, osteoclast proliferation and activation have been identified (1-5). It is now recognised that signalling via the constitutively expressed Receptor Activator of NF-κB (RANK) on osteoclast precursors following binding to RANK ligand (RANKL), in conjunction with activation by macrophage-colony stimulating factor (M-CSF), results in a complex series of events leading to the production of mature osteoclasts. In vivo both M-CSF and RANKL are provided by osteoblasts, which, together with the decoy receptor osteoprotegerin (OPG) (6-7), serve to regulate osteoclast differentiation and bone resorption. It is via the osteoblast component that systemic hormones and cytokines act indirectly to influence this process, with the relative ratio of RANKL to OPG critically controlling osteoclastogenesis. In pathological states (such as rheumatoid arthritis (RA)) however, RANKL can be provided additionally by activated T cells, fibroblast-like synoviocytes and other stromal cells (8-10). RANKL-RANK binding activates cell signalling cascades through several key stages. The process relies on the recruitment of TNF receptor-associated factor proteins (TRAFs), mitogen-activated protein kinase cascades (ERK, JNK and p38) in addition to Src- and phosphatidylinositol-3-kinase (PI3K) mediated activation of Akt, and all these RANK signalling pathways ultimately converge to activate several transcription factor families—such as NF-κB (11), activator protein-1 (AP-1) (12), particularly c-Fos (13), and Nuclear Factor of Activated T cells (NFAT), specifically NFATc1 (1;5;14;15). That these signalling molecules and transcription factors have essential roles in osteoclast differentiation and activation has been demonstrated unequivocally in loss-of-function mouse mutants in vivo (5).
The anti-inflammatory properties of a human molecular chaperone known variously as binding immunoglobulin protein (BiP) or glucose regulated protein (Grp)78 have been reported (17). The gene encoding BiP has been cloned and the recombinant human (rhu) protein expressed (WO 00/21995).
Administration of rhuBiP to mice with collagen-induced arthritis (CIA), prevented the induction of experimental arthritis (17). An indication of the anti-inflammatory mechanism of action of BiP, was the finding that T cell clones responsive to rhuBiP produced the cytokines, IL-10, IL-4 and IL-5 (18) and that BiP-stimulated peripheral blood (PB) mononuclear cells (MC) produced high concentrations of IL-10 with concomitant attenuation of TNF-α production. PBMC also produced increased amounts of IL-1R antagonist and soluble TNFRII (19). Cytokines released from PBMC in response to BiP regulate osteoclastogenesis (20;21).
To reinforce the fact that these extracellular functions of BiP have biological relevance, immunoassay of synovial fluids has revealed that the majority of those from patients with RA contain soluble BiP (19). It is also known that the antigen presenting function of monocytes (MO) is reduced following downregulation of CD86 and HLA-DR expression (19) and that BiP delays and prevents the maturation of purified PBMO into immature dendritic cells (iDC) (22).
The use of BiP in the manufacture of a medicament for the treatment of an unwanted immune response is described in WO02/072133.
Bone is continually made or digested by specialist cells called osteoblasts and osteoclasts respectively. There are many diseases in which bone erosion or thinning occurs due to an imbalance between bone formation and bone dissolution. Accordingly, there is a need in the art to develop drugs that modulate (e.g. prevent) this process.